methyl 2,6-dihydroxybenzoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Concentrated sulfuric acid (40 ml) was carefully added to a solution of 2,6-dihydroxybenzoic acid (133 g, 0.86 mol) in absolute methanol (500 ml). The reaction mixture was heated at reflux temperature for 24 hours, cooled, and evaporated. The residue was added to aa saturated sodium hydrogencarbonate solution, and the resulting solid was collected by filtration, washed with water, and dried in vacuo over phosphorus peroxide; yield 49 g (34%). NMR (CDCl3, 60 MHz): δ4.02 (s, CO2CH3) p.p.m. The reaction mixture was heated at reflux temperature for 24 hours cooled evaporated The residue was added to aa saturated sodium hydrogencarbonate solution the resulting solid was collected by filtration washed with water dried in vacuo over phosphorus peroxide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 2,6-dihydroxybenzoate (1.0 g, 5.95 mmol) and 4-(Boc-amino)-1-butanol (1.1 mL, 5.95 mmol) in 60 mL of THF is added PPh3 (1.7 g, 6.5 mmol) and DEAD (2.97 mL, 6.5 mmol). The solution is stirred at RT for 18 h then the solvent is removed under reduced pressure. The residue is purified by flash chromatography using a gradient of hexane/EtOAc (5:1 to 2:1) to give the product as a colorless liquid. the solvent is removed under reduced pressure The residue is purified by flash chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluorobenzaldehyde (1.00 g, 8.06 mmol) and methyl 2,6-dihydroxybenzoate (2.03 g, 12.1 mmol) were dissolved in N,N-dimethylformamide (50 mL) and potassium carbonate (1.11 g, 8.06 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was diluted with water (25 mL) and the layers separated. The aqueous phase was extracted twice with ethyl acetate (25 mL) then twice with diethyl ether (50 mL). The organic phases were combined and dried over MgSO4. The solution was filtered and the solvent evaporated then placed under high vacuum. The mixture was chromatographed, eluted with 25–50% ethyl acetate/hexanes. The desired fractions were combined and concentrated to give a light yellow oil. The product was redissolved in a minimum amount of dichloromethane, triturated with hexane and the solvent evaporated to give an oily yellow solid (0.21 g, 9%). 1H NMR (400 MHz, CDCl3): δ 9.93 (s, 1H), 7.84 (m, 2H), 7.38 (t, J=8.4 Hz, 1H), 7.08 (m, 2H), 6.81 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H); LCMS found for C16H15O5 (M+H)+: m/z=287.0. the layers separated The aqueous phase was extracted twice with ethyl acetate (25 mL) dried over MgSO4 The solution was filtered the solvent evaporated The mixture was chromatographed eluted with 25–50% ethyl acetate/hexanes concentrated to give a light yellow oil triturated with hexane the solvent evaporated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4.08-C (0.21 g, 0.6 mmol), methyl 2,6-dihydroxybenzoate (0.13 g, 0.8 mmol), and triphenylphosphine (0.22 g, 0.8 mmol) in tetrahydrofuran (1.5 mL) was treated with diisopropyl azodicarboxylate (0.18 mL, 0.9 mmol) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated to give a crude residue which was purified using flash column chromatography (100% hexane to 25% ethyl acetate/hexane) to yield 4.08-D as a white solid (0.18 g, 60%). 1H NMR (500 MHz, CDCl3): δ 11.47 (s, 1H), 7.42 (dd, J=8.3, 8.3 Hz, 1H), 7.34–7.31 (m, 3H), 7.11–7.08 (m, 1H), 6.62 (s, 1H), 6.60 (dd, J=8.3, 1.0 Hz, 1H), 6.43 (dd, J=8.3, 1.0 Hz, 1H), 4.27–4.25 (m, 2H), 4.21–4.19 (m, 2H), 3.91 (s, 3H), 2.33–2.30 (m, 2H), 1.73 (s, 9H); LCMS found for C24H27NO8SNa (M+Na)+: m/z=512. The reaction mixture was concentrated to give a crude residue which was purified to yield 4.08-D as a white solid (0.18 g, 60%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 2,6-dihydroxybenzoate (1.0 g, 5.95 mmol) and 4-(Boc-amino)-1-butanol (1.1 mL, 5.95 mmol) in 60 mL THF is added PPh3 (1.7 g, 6.5 mmol) and DEAD (2.97 mL, 6.5 mmol) and the mixture is stirred at RT overnight. The solvent is removed under reduced pressure and the residue is purified by flash chromatography eluting with hexanes/EtOAc (5:1 to 2:1) to give the title compound as a colorless liquid: 1H NMR (CDCl3) δ 11.42 (s, 1H), 7.29 (t, J=8.34 Hz, 1H), 6.57 (d, J=8.34 Hz, 1H), 6.37 (d, J=8.34 Hz, 1H), 4.63 (s, 1H), 3.99 (t, J=6.06 Hz, 2H), 3.93 (s, 3H), 3.22-3.17 (m, 2H), 1.88-1.81 (m, 2H), 1.74-1.67 (m, 2H), 1.43 (s, 9H); (M−1)−=338. The solvent is removed under reduced pressure the residue is purified by flash chromatography eluting with hexanes/EtOAc (5:1 to 2:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of methyl-2,6-dihydroxybenzoate (1.68 g, 10.0 mmol) in dichloromethane (10 mL) was added acetic acid (1 mL), followed by drop-wise addition of bromine (515 μL, 10.0 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at ambient temperature for 1 hour, concentrated under reduced pressure, co-evaporated with ethyl acetate (2×). The resulting solid was triturated with hexane/ethyl acetate and re-crystallized from hot hexane/ethyl acetate to provide the titled compound (1.45 g). MS ESI(−,) m/e 244, 246 (M−H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 10.19 (s, 1H), 7.46 (d, 1H), 6.41 (d, 1H), 3.84 (s, 3H). concentrated under reduced pressure, co-evaporated with ethyl acetate (2×) The resulting solid was triturated with hexane/ethyl acetate re-crystallized from hot hexane/ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir: